| Project/Area Number |
15K09442
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | Wakayama Medical University (2018)
Jichi Medical University (2015-2017) |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 摂食行動 / 室傍核 / Nesfatin-1 / FGF21 / メタボリックシンドローム / 弓状核 / 概日リズム / 摂食調節 / エネルギー代謝 / 生活習慣病 / 時計遺伝子 / NUCB2/Nesfatin-1 / BMAL1 / AgRP / Oxytocin / NUCB2 |
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| Outline of Final Research Achievements |
Nesfatin-1, an anorectic peptide processed from nucleobindin-2 (NUCB2), is expressed in the hypothalamus including the paraventricular nucleus (PVN). PVN specific NUCB2 knockdown induces LP-selective hyperphagia and reduction of PVN Oxt mRNA expression as early as 3-4 weeks after AAV treatment, which were followed by increases in daily food intake and body weight in later period. These results reveal that the endogenous nesfatin-1 neuron in PVN regulates PVN oxytocin and consequently the energy balance. Furthermore, we clarified that fibroblast growth factor (FGF) 21 is a novel regulator of nesfatin-1 neurons. ICV injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 failed to suppress food intake in PVN-preferential Nucb2 knockout mice. These results demonstrate that the PVN nesfatin-1 neurons physiologically sense key peripheral metabolic signals, and thereby regulate circadian feeding rhythm and glucose metabolism.
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| Academic Significance and Societal Importance of the Research Achievements |
生活リズムの乱れ、特に食行動リズムの乱れは生活習慣病を増悪させる。食行動リズムの形成機構を解明することは、生活習慣病の病態の解明および予防・治療に有用である。本研究では、食行動リズムは、室傍核Nesfatin1ニューロンの活動リズムが制御する事を示した。さらにNesfatin-1ニューロンの上流はFGF21、下流はOxytocinニューロンである事も示した。この結果から、FGF21、Nesfatin-1、Oxytocinを標的とした生活習慣病の予防・治療法確立への展開が期待できる。さらに、弓状核-室傍核軸を切り口として血圧制御機構の分子基盤を与え、治療介入点を示すことが出来た。
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